Excessive hepatic glucose production (HGP) and defective insulin signaling are critical in the development of type 2 diabetes (T2D). Over the past few years, our work has revealed new molecular pathways relevant to these two processes?pathways that we have shown recently in pre-clinical studies are amenable to a new type of therapy. We showed that obesity leads to the activation of a pathway initiated by calcium-induced activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes (HCs). CaMKII suppresses an ATF6-protein chaperone module, which in turn activates a PERK-ATF4-Trb3 pathway that disrupts insulin receptor signaling. Our new data has revealed that hepatic CaMKII phosphorylates and blocks nuclear translocation of a class IIa histone deacetylase (HDAC4), which increases the level of a co- repressor called Dachshund homolog 1 (Dach1). Dach1, which has never before been implicated in metabolism, is dramatically increased in the livers of obese mice and humans and its inhibition in obese mice protects against hyperglycemia and hyperinsulinemia, identifying Dach1 as a critical link between obesity, insulin resistance, and metabolic dysfunction. We have proposed a series of studies to determine the mechanisms by which hepatocyte Dach1 deficiency improves insulin resistance in obesity (Aim 1) and to elucidate the proximal signaling events of how obesity regulates Dach1 and the downstream molecular mechanisms of Dach1-mediated suppression of insulin signaling (Aim 2). The involvement of hepatic Dach1 in the metabolic disturbances of obesity is a completely new and unexplored concept. We believe upon completion of the proposed studies, the integrated role of hepatic Dach1 in mediating insulin resistance through its effects on insulin signaling could reveal novel insights and provide therapeutic strategies for the treatment of T2D.